Chiral heterocyclic β-enamino esters: Convenient synthesis and diastereoselective reduction

Article abstract of DOI:10.1016/S0040-4020(03)00980-3

The preparation of chiral pyrrolidine and piperidine β-enamino esters starting from ω-halogeno β-keto esters, their diastereoselective reduction and the subsequent cleavage of the chiral auxiliary are described.

Full text of DOI:10.1016/S0040-4020(03)00980-3

Tetrahedron 59 (2003) 6333–6339
Chiral heterocyclic b-enamino esters: convenient synthesis
and diastereoselective reduction
´
Sandrine Calvet, Olivier David, Corinne Vanucci-Bacque, Marie-Claude Fargeau-Bellassoued
*
´
and Gerard Lhommet
´ ´ ´ ´
Laboratoire de Chimie des Heterocycles, associe au CNRS, Universite Pierre et Marie Curie, UMR 7611, 4 Place Jussieu,
F-75252 Paris cedex 05, France
Received 6 March 2003; revised 22 May 2003; accepted 16 June 2003
Abstract—The preparation of chiral pyrrolidine and piperidine b-enamino esters starting from v-halogeno b-keto esters, their
diastereoselective reduction and the subsequent cleavage of the chiral auxiliary are described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
with various amines in the presence of catalytic iodine as a
catalyst, sodium sulfate as a drying agent and disodium
hydrogen phosphate as an acid scavenger (Scheme 2). Thus
methyl 6-chloro-3-oxohexanoate6 was reacted under these
conditions with (S)-1-phenylethylamine or (S)-phenylglyci-
nol yielding the expected compounds 1a and 1b, respect-
ively, along with about 10% of the tetrahydrofuranyl
derivative 2 resulting from the O-cycloalkylation of the
starting chloro ester.7 A simple acid-base workup followed
by flash chromatography on silica gel gave 1a and 1b in 60
and 57% yield, respectively.
During the course of our research toward the preparation of
chiral polyfunctional heterocycles as precursors of natural
products, we are interested in developing new methods able to
spare sacrificial chiral auxiliaries by their introduction in a late
stage of the synthesis. In a recent publication,1 we described a
convenient preparation of chiral pyrrolidine and piperidine
b-enamino esters whose reduction products often constitute
valuable intermediates in the synthesis of alkaloids.2 This
one-stepprocedurewhichinvolvesthecondensationofmethyl
v-halogeno alcynoates and (S)-1-phenylethylamine or
(S)-phenylglycinol (Scheme 1, route a), provides an interest-
ing alternative to the Eschenmoser reaction,3 (Scheme 1, route
b) in which phosphorus-containing reagents may be trouble-
some.4 We wish now to report our study concerning the
condensation of the same chiral amines with v-halogeno
b-keto esters in place of the previously used but expensive
alcynoates (Scheme 1, route c) to lead to various cyclic
b-enamino esters. A study aimed at reducing the enamine
moiety will be presented in a second part.
We then extended these results to the synthesis of the
piperidine enamino esters 3 starting from methyl 7-chloro-
3-oxoheptanoate.6 However, condensation of the latter with
(S)-1-phenylethylamine, in the conditions described above,
exclusively afforded the undesired cyclohexene 58 as the
only identifiable product (Scheme 3, conditions (a)).
Analysis of the potential reactivity of 7-chloro-3-oxohep-
tanoate under the reaction conditions, indicates that this
2. Results and discussion
2.1. Synthesis of chiral b-enamino esters
We first planed to synthesize pyrrolidine enamino esters 1
through an extension of a previously reported procedure5 in
which the authors reacted ethyl 6-chloro-3-oxohexanoate
Keywords: pyrrolidine; piperidine; enamino ester; b-keto ester; reduction;
debenzylation.
*
Corresponding author. Fax: þ33-1442-73056;
e-mail: lhommet@ccr.jussieu.fr
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00980-3

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S. Calvet et al. / Tetrahedron 59 (2003) 6333–6339
Scheme 2.
halogeno b-keto ester may evolve according to two
competitive pathways, i.e. either into a v-amino b-keto
ester stemming from the initial substitution of the halogen
by the chiral amine or into an enamine resulting from the
reaction of the amine on the keto moiety. Our result clearly
demonstrates that the latter intermediate is favored leading
to compound 5 by a C-cycloalkylation process. It is
noteworthy to mention that, in our previous alcynoate
strategy,1 we encountered similar problems that we finally
overcame by replacing the chlorine by an iodine atom. This
result prompted us to perform the reaction starting from
methyl 7-iodo-3-oxoheptanoate readily obtained by treat-
ment of the chloro analogue with NaI in refluxing acetone.
However, 5 remained the only detected reaction product.
The reaction was then attempted under conditions similar to
those optimized with the alcynoates.1 Thus, the iodo
derivative was treated with an equimolar amount of (S)-1-
phenylethylamine, in the presence of sodium carbonate
(5 equiv.) and a catalytic amount of tetrabutylammonium
iodide, in refluxing acetonitrile for 24 h. These reaction
conditions led to the obtention of a mixture of the expected
compound 3a along with cyclohexene 5 and the tetrahy-
dropyranyl derivative 49 in a disappointing 25:55:20 ratio
(Scheme 3, conditions (a)). Under these reaction conditions,
the formation of the enolate of the b-keto ester is the first
reaction to occur.10 This intermediate may then evolve
along three competitive pathways: either an O-cycloalkyla-
tion (as previously observed for the formation of 2) to afford
compound 4 (path i), or a C-cycloalkylation giving rise to
cyclohexene 5 via the cyclic b-keto ester 611 (path ii) or
halogen displacement by the amine allowing the formation
of the expected amino ester 3a (path iii).
In view of this analysis, we reasoned that initial protection
of the keto function of methyl 7-chloro-3-oxoheptanoate
would prevent the generation of the enolate that was
suspected to be the key intermediate of the observed side-
products. Methyl 7-chloro-3-oxoheptanoate was thus
readily converted into the corresponding dioxolane 7 in
82% yield. Subsequent substitution of the halogen moiety
by (S)-1-phenylethylamine was achieved in refluxing
acetonitrile in the presence of sodium iodide to promote
the in situ halogen exchange, to afford amino dioxolane 8a
in 97% crude yield (Scheme 4).
At this point, we realized that the deprotection step of the
dioxolane moiety could be followed by the in situ formation
of the expected piperidine enamino ester 3a. With this goal
Scheme 3. Conditions (a) Na2SO4, Na2HPO4, [I2]; (b) Na2CO3, [TBAI], CH3CN.

S. Calvet et al. / Tetrahedron 59 (2003) 6333–6339
6335
Scheme 4.
in mind, we screened various acidic conditions. The use of
either Dowex 50 resin in acetone or p-TSA, in acetone or
methanol, left the substrate unchanged. Treatment with an
aqueous 1N HCl solution provided the expected compound
3a along with the undesired linear decarboxylation product
9 (Figure 1). The relative ratio of these two products
depended on the reaction time, the temperature and the
amount of acid. A brief study was carried out to optimize the
amount of 3a. The best result was obtained upon using
5 equiv. of HCl solution, for 11 h, at room temperature.
Under these conditions, 3a was isolated in 46% yield after
chromatography on silica gel. Only a trace of 9 was detected
in the reaction mixture. Finally, we discovered that
borontrifluoride etherate12 provided milder conditions
while preventing the decarboxylation process: the expected
compound 3a was thus cleanly obtained in 74% yield
(Scheme 4).
1b. However, the overall yields from methyl-6-chloro-3-
oxohexanoate (57 and 47%, respectively) were not better
than those obtained by the direct route.
2.2. Diastereoselective reductions
The pyrrolidines and piperidines thus obtained might be
intermediates in the chiral synthesis of natural products
following a diastereoselective reduction of the enamine/he-
miaminal moiety and the subsequent cleavage of the chiral
auxiliary. As far as the 1(S)-phenylethyl N-substituted b-
enamino esters 1a and 3a are concerned, this strategy has
already been studied by us and others.14 However, this was
not the case for the phenylglycinol derivatives 1b and 10
and we therefore decided to extend the scope of this strategy
from these substrates. The reduction of the C–C double
bond of the pyrrolidine substrate 1b was first carried out
either by catalytic hydrogenation or using an hydride in
order to compare the resulting diastereoselectivity. Catalytic
hydrogenation was performed under an atmospheric press-
ure of hydrogen using PtO2 as the catalyst to yield
quantitatively the expected amino ester 12 with a 90%
diastereomeric excess (Scheme 6). Triacetoxyborohydride
mediated reduction15 proceeded cleanly but with a lower
selectivity (d.e.¼70%). These results were similar to those
obtained under similar conditions from 1a. Noteworthy was
the degradation of 12 upon silica gel chromatography to
lead, among others, to a lactone derivative as a consequence
of an intramolecular transesterification. The major diaster-
eomer 12 was alternatively easily isolated by simple
crystallization in cyclohexane,16 in 53% yield. At this
point, X-ray analysis17 was performed and indicated a 2S
assignment to the absolute configuration of the newly
This optimized strategy was then applied to (S)-phenylgly-
cinol (Scheme 5). In this case, the substitution step from
dioxolane 7 led to compound 8b in 95% crude yield,
whereas the deprotection–cyclisation step, under the
borontrifluoride etherate conditions, directly delivered the
bicyclic derivative 10, in 67% yield, as an inseparable 90:10
mixture of diastereomers, rather than the expected enam-
inoester 3b, as previously observed.1 Noteworthy was the
formation of the decarboxylation compound 11 (Figure 1) as
a mixture of diastereomers when the reaction was carried
out under uncontrolled acidic conditions or when compound
10 was treated in acidic medium. A study of the spectro-
scopic data of the major isomer of 11 allowed us to assign a
cis relationship between the phenyl group and the angular
methyl substituent.13 By extension, we can then ascribe the
same relative configuration for the major isomer of
compound 10 (Scheme 5).
It is to be noted that in order to avoid the formation of the
tetrahydrofuranyl derivative 2, this multi-step procedure
involving a protecting step of the keto function was equally
applied to the formation of pyrrolidine compounds 1a and
Figure 1.
Scheme 5.

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S. Calvet et al. / Tetrahedron 59 (2003) 6333–6339
Scheme 6.
reduction of 3a,14c the debenzylation step proceeded
smoothly under catalytic hydrogenation, on Pd(OH)2/C, to
give quantitatively rise to methyl piperidine-2-yl acetate
15.19 However, to our knowledge, literature does not
mention any specific rotation for amine 15, but for its N-
tert-butoxycarbonyl derivative 16.20 Therefore, we trans-
formed crude 15 into compound 16 in 90% overall
chromatographed yield. Comparison of the spectroscopic
data of the resulting compound20 with the one described in
the literature allowed us to secure the absolute configuration
of 15 (and so of 14) as 2(S). The stereochemistry of the
major isomer of 14 results indeed from a favored approach
of the hydrogen on the Re face of the iminium intermediate,
in which 1,3-allylic strain is minimized (Scheme 7).
3. Conclusion
In conclusion, we have developed efficient alternative
procedures for preparing enantiopure heterocyclic enamino
esters from v-halogeno b-keto esters and chiral amines. The
compounds stemming from (S)-phenylglycinol have been
reduced yielding with a high diastereoselectivity the
corresponding amino esters, from which the chiral auxiliary
moieties were subsequently smoothly removed. This
strategy constitutes a valuable tool for the alkaloid synthesis
and compares favorably with previously reported pro-
cedures in terms of cost, work up and ease of purification.
Figure 2. Crystal structure of 12.
created stereocenter (Figure 2). Finally, debenzylation of 12
was readily achieved under an atmospheric pressure of
hydrogen on Pd(OH)2/C affording quantitatively amino
ester 13.18
Concerning the diastereomeric mixture of bicyclic piper-
idine 10, it should be stressed that catalytic hydrogenation
over PtO2 did not take place under neutral conditions.
However, when performed in the presence of a catalytic
amount of p-TSA, the expected compound 14 was obtained
with a diastereomeric excess of 70%. This result suggested
that the reaction proceeded through the reduction of an
iminium intermediate. Improved results were observed
upon triacetoxyborohydride reduction (Scheme 7). In this
case, compound 14 was obtained as a mixture of
diastereomers (d.e.¼90%), in 93% yield, after column
chromatography. The major isomer was isolated, in 63%
yield, as an oil, following a second chromatography on
silica gel. In contrast with the amino ester resulting from the
4. Experimental
4.1. General
Melting points were determined using a Buchi 535
apparatus and are uncorrected. IR spectra were recorded
1
with a Philips PU 9706 spectrometer. H and 13C NMR
spectra were recorded in CDCl3 as solvent on a Bruker ARX
250 spectrometer with TMS or CHCl3 as internal standard.
The values of chemical shifts (d) are given in ppm and
Scheme 7.

S. Calvet et al. / Tetrahedron 59 (2003) 6333–6339
6337
coupling constants (J) in Hertz. Optical rotations were
measured with a Perkin–Elmer 241 polarimeter. Elemental
Spectroscopic data in total agreement with those reported in
the literature.1
´
analyses were performed by the Service Regional de
Microanalyse de L’Universite Pierre et Marie Curie.
´
4.1.4. Methyl-6-chloro-3-oxoheptanoate. The title com-
pound was prepared in a manner similar to that described for
the hexanoate analogue, using 1-bromo-2-chloropropane as
the alkylating agent. Column chromatography of the crude
product using ethyl acetate/cyclohexane 1:9 as the eluent
afforded the expected compound (7.5 g, 71%) as a colour-
less oil. 1H NMR d: 1.72–1.82 (m, 4H); 2.60 (t, 2H,
J¼7 Hz); 3.46 (s, 2H); 3.54 (t, 2H, J¼7 Hz); 3.74 (s, 3H).
13C NMR d: 20.5; 31.5; 41.8; 44.5; 48.8; 52.2; 167.5; 202.0.
IR (neat) nmax 3500, 1750, 1720, 1630 cm21. Anal. calcd for
C8H13ClO3: C, 49.88; H, 6.80. Found: C, 49.92; H, 6.93.
HRMS were obtained on a JEOL MS 700 mass spec-
trometer. Column chromatography was performed on Merk
Kieselgel silica gel (230–400 mesh). All reactions were
carried out in an argon atmosphere. Anhydrous CH2Cl2 was
distilled from CaH2. Anhydrous THF was distilled from
sodium/benzophenone under nitrogen.
4.1.1. Methyl-6-chloro-3-oxohexanoate. To an ice-cooled
stirred suspension of NaH (60% in oil, 2.2 g, 55 mmol) in
anhydrous THF (100 mL) under argon was added dropwise
methylacetoacetate (6.42 g, 55 mmol). The reaction mixture
was stirred at 08C for 30 min, afterwards n-BuLi (23.2 mL,
2.5 M solution in hexane, 58 mmol) was slowly added.
After stirring for 30 min, the reaction mixture was cooled to
2308C, and 1-bromo-2-chloroethane (4.5 mL, 55 mmol)
was added and stirring was continued at this temperature for
15 h. The mixture was then quenched by addition of
saturated aqueous NH4Cl solution (50 mL) and allowed to
warm to room temperature. The reaction mixture was
concentrated in vacuo and extracted with CH2Cl2 (150 mL).
The organic layer was washed successively with saturated
aqueous NH4Cl solution (50 mL), water (50 mL) and brine
(50 mL), dried over Na2SO4 and concentrated in vacuo.
Column chromatography eluting with ethyl acetate/cyclo-
hexane 1:9 yielded the title compound as a colorless oil
4.1.5. [2-(4-Chlorobutyl)-[1,3]dioxolan-2-yl]-acetic acid
methyl ester (7). A mixture of methyl-6-chloro-3-oxohep-
tanoate (2 g, 10.4 mmol), methyl orthoformate (3.45 mL,
20 mmol), ethyleneglycol (2.9 mL, 52 mmol) and p-TSA
(0.19 g, 1 mmol) was stirred at room temperature for 6 h.
Then a 5% aqueous solution of NaH2PO4 (3 mL) was added
and the reaction mixture was stirred for 15 min. Et2O
(100 mL) was then added and the organic layer was washed
twice with water (25 mL) and brine (25 mL) then dried over
Na2SO4 and concentrated in vacuo. Column chromato-
graphy eluted with ethyl acetate/cyclohexane 2:8 afforded
the title compound (2.1 g, 82%). Rf¼0.3 (ethyl acetate/
cyclohexane 2:8).1H NMR d: 1.51–1.62 (m, 2H); 1.75–
1.88 (m, 4H); 2.66 (s, 2H); 3.54 (t, 2H, J¼6.5 Hz); 3.70 (s,
3H); 3.96–4.02 (m, 4H). 13C NMR d: 20.7; 32.4; 36.6; 42.3;
1
(6.5 g, 66%). Rf¼0.31 (ethyl acetate/cyclohexane 2:8). H
NMR d: 2.07 (quint., 2H, J¼6.5 Hz); 2.75 (t, 2H, J¼7 Hz);
3.55 (s, 2H); 3.57 (t, 2H, J¼6.5 Hz); 3.73 (s, 3H). 13C NMR
d: 23.4; 39.2; 43.8; 48.5; 51.8; 167.1; 201.4. IR (neat) nmax
1740, 1710 cm21. Anal. calcd for C7H11ClO3: C, 47.07; H,
6.21. Found: C, 47.01; H, 6.33.
44.7; 51.6; 65.0; 108.9; 169.8. IR (neat) nmax 1735 cm21
.
Anal. calcd for C10H17ClO4: C, 50.74; H, 7.24. Found: C,
50.62; H, 7.36.
4.1.6. {2-[4-(1-(S)-Phenylethylamino)-butyl]-[1,3]dioxo-
lan-2-yl}acetic acid methyl ester (8a). To a solution of 7
(0.76 g, 3.2 mmol) in acetonitrile (50 mL) was added NaI
(0.482 g, 3.2 mmol), Na2CO3 (1.7 g, 16 mmol), tetrabutyl-
ammonium iodide (0.118 g, 0.3 mmol) and (S)-1-phenyl-
ethylamine (0.389 g, 3.2 mmol). The reaction mixture was
heated under reflux for 48 h, then allowed to cool to room
temperature. Evaporation of the solvent was followed by
extraction of the residue with Et2O (3£25 mL). The
combined organic layer was washed with brine (20 mL),
dried over Na2SO4 and concentrated in vacuo to afford the
title compound (1 g, 97%) as an oil. Due to the instability of
this compound on silica gel, it was not further purified but
the crude product was pure enough to be directly engaged in
the next step. 1H NMR d: 1.30–1.54 (m, 4H); 1.38 (d, 3H,
J¼6.5 Hz); 1.74–1.81 (m, 2H); 2.37–2.60 (m, 2H); 2.64 (s,
2H); 3.68 (s, 3H), 3.78 (q, 1H, J¼6.5 Hz); 3.92–3.99 (m,
4H); 7.22–7.35 (m, 5H). 13C NMR d: 21.3; 24.4; 30.0; 37.5;
42.5; 47.6; 51.8; 58.5; 65.2; 109.3; 126.7; 127.0; 128.5;
148.8; 170.0. IR (neat) nmax 3400 (w), 1740 cm21. HRMS
(CI) calcd for C18H28NO4 (MHþ): 322.2018. Found:
322.2021.
4.1.2. [1-(1-(S)-Phenyl-ethyl)-pyrrolidin-2-ylidene]-
acetic acid methyl ester (1a). To a mixture of methyl 6-
chloro-3-oxohexanoate (1.4 g, 7.55 mmol) and (S)-1-phe-
nylethylamine (1 mL, 7.55 mmol) was added a crystal of
iodine, Na2HPO4 (1.1 g, 7.55 mmol) and Na2SO4 (1.1 g,
7.55 mmol). The reaction mixture was heated at 658C for
90 h. After cooling to room temperature, CH2Cl2 (100 mL)
was added and the organic layer was washed with water
(35 mL). The aqueous layer was extracted with CH2Cl2
(3£15 mL). The combined organic layer was then extracted
with 2N aqueous HCl solution (3£30 mL). The latter
aqueous combined layer was basified by careful addition
of solid K2CO3 and then extracted with CH2Cl2 (3£30 mL)
The combined organic layer was dried over Na2SO4 and
concentrated in vacuo. Column chromatography eluted with
ethyl acetate/cyclohexane 2:8 afforded the title compound
(1.1 g, 60%) as a white solid. Rf¼0.2 (ethyl acetate/
cyclohexane 2:8). Spectroscopic data are in total agreement
with those reported in the literature.1
4.1.3. [2-Hydroxy-1-(S)-phenyl-ethyl)-pyrrolidin-2-yli-
dene]-acetic acid methyl ester (1b). The title compound
was obtained following a procedure similar to the one
described for compound 1a, using (S)-phenylglycinol as the
amine. Column chromatography of the crude mixture eluted
with ethyl acetate/cyclohexane 4:6 afforded compound 1b
(57%) as a solid. Rf¼0.4 (ethyl acetate/cyclohexane 8:2).
4.1.7. {2-[4-(2-Hydroxy-1-(S)-phenylethylamino)-butyl]-
[1,3]dioxolan-2-yl}acetic acid methyl ester (8b). The title
compound 8b was obtained as an oil (1.02 g, 95%) in a
manner similar to the one described for 8a using (S)-
phenylglycinol as the amine. Due to the instability of this
compound on silica gel, it was not further purified but the

6338
S. Calvet et al. / Tetrahedron 59 (2003) 6333–6339
crude product was pure enough to be directly engaged in the
1
next step. H NMR d: 1.41–1.50 (m, 4H); 1.75–1.79 (m,
3.60 (dd, 1H, J¼7.8 and 7.5 Hz); 3.90 (t, 1H, J¼7.5 Hz);
4.18 (t, 1H, J¼7.8 Hz); 7.25–7.41 (m, 5H). 13C NMR d:
13.8; 22.0; 25.5; 36.9; 43.1; 62.6; 71.9; 93.2; 127.6; 127.8;
128.5; 140.5.
2H); 2.49–2.60 (m, 2H); 2.64 (s, 2H); 3.48–3.56 (m, 1H);
3.67 (s, 3H); 3.67–3.77 (m, 2H); 3.92–3.99 (m, 4H); 7.25–
7.38 (m, 5H). 13C NMR d: 21.1; 30.0; 37.4; 42.4; 47.1; 51.8;
64.6; 65.1; 66.5; 109.2; 127.2; 127.6; 128.7; 140.7; 170.0.
IR (neat) nmax 3400, 1730 cm21. HRMS (CI) calcd for
C18H28NO5 (MHþ): 338.1967. Found: 338.1971.
4.1.12. (2S)-[1-(2-Hydroxy-1-(S)-phenyl-ethyl)-pyrroli-
din-2-yl]-acetic acid methyl ester (12). Compound 1b
(90 mg, 0.34 mmol) in methyl acetate (10 mL) was
subjected to hydrogenation (1 atm) in the presence of
PtO2 (18 mg) at room temperature for 24 h. The mixture
was then filtered over a Celitew pad and the solvent was
evaporated in vacuo yielding the title compound (91 mg,
99%) as a 95:5 diastereomeric mixture. Crystallization from
cyclohexane afforded the pure major isomer (47 mg, 53%)
as colorless crystals. Rf¼0.4 (ethyl acetate/cyclohexane
4.1.8. [1-(1-(S)-Phenyl-ethyl)-piperidin-2-ylidene]-acetic
acid methyl ester (3a). To a cooled solution of compound
8a (119 mg, 0.37 mmol) in CH2Cl2 (30 mL) at 08C was
added drop wise BF3–Et2O (0.45 mL, 3.7 mmol). The
reaction mixture was stirred at this temperature for 15 h then
quenched with saturated NaHCO3 aqueous solution
(15 mL). The reaction mixture was allowed to warm to
room temperature, then extracted with CH2Cl2 (4£15 mL).
The combined organic layer was dried over Na2SO4 and
concentrated in vacuo. Column chromatography eluted with
ethyl acetate/cyclohexane 2:8 afforded the title compound
3a (96 mg, 74%) as a white solid. Rf¼0.3 (ethyl acetate/
cyclohexane 2:8). Spectroscopic data are in total agreement
with those reported in the literature.1
1
8:2). H NMR d: 1.51–1.76 (m, 5H); 2.12–2.38 (m, 2H);
2.73–2.79 (m, 1H); 2.96–3.02 (m, 1H); 3.37–3.41 (m, 1H);
3.62 (s, 3H); 3.72–3.97 (m, 3H); 7.26–7.39 (m, 5H). 13C
NMR d: 23.1; 30.8; 40.0; 51.5; 52.0; 56.6; 63.6; 67.8; 127.8;
128.5; 128.7; 139.2; 172.7. [a]2D0¼þ11 (c 1.09, CHCl3). Mp
688C. IR (CHBr3) nmax 3400, 1730 cm21. Anal. calcd for
C15H21NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 69.07; H,
7.39; N, 5.29.
4.1.9. 6-(1-(S)-Phenyl-ethylamino)-hexan-2-one (9).
Compound 3a (101 mg, 0.4 mmol) was stirred in 1N HCl
aqueous solution (15 mL) for 15 h at room temperature. The
reaction mixture was basified by careful addition of solid
Na2CO3 and extracted with CH2Cl2 (3£15 mL). The
combined organic layer was washed with brine (20 mL)
dried over Na2SO4 and concentrated in vacuo yielding the
title compound (72 mg, 85%). Due to the instability of this
compound on silica gel, it was not further purified. 1H NMR
d: 1.34 (d, 3H, J¼6.5 Hz); 1.40–1.63 (m, 4H); 2.11 (s, 3H);
2.36–2.52 (m, 4H); 3.74 (q, 1H, J¼6.5 Hz); 7.20–7.34 (m,
5H). 13C NMR d: 21.2; 23.0; 28.2; 29.9; 43.2; 46.7; 58.5;
127.0; 127.6; 128.7; 142.6; 208.8. IR (neat) nmax 3320 (w),
4.1.13. (2S)-Pyrrolidine-2-yl-acetic acid methyl ester
(13). Compound 12 (0.6 g, 2.27 mmol) in methanol
(30 mL) was subjected to hydrogenation (1 atm) in the
presence of Pd(OH)2/C (0.3 g) at room temperature for 1 h.
The mixture was then filtered over a Celitew pad and the
solvent was evaporated in vacuo. The residue was dissolved
in CH2Cl2 (50 mL) and the organic layer was extracted with
2N aqueous HCl solution (2£25 mL). The combined
aqueous layer was basified by careful addition of solid
K2CO3 and extracted with CH2Cl2 (3£25 mL) The com-
bined organic layer was washed with brine (20 mL) and
dried over Na2SO4. Evaporation of the solvent in vacuo
afforded the title compound (0.23 g, 70%) as an oil whose
spectroscopic data are consistent with those reported in the
literature.18
1710 cm21
.
4.1.10. 8a-Methyl-3-(S)-phenyl-hexahydro-oxazolo[3,2-
a]pyridine (10). The title compound 10 (153 mg, 67%)
was obtained as an inseparable 9:1 diastereomeric mixture
in manner similar to the one described for 3a, starting from
compound 8b (279 mg, 8 mmol). Rf¼0.3 (ethyl acetate/
cyclohexane 2:8). Spectroscopic data are in total agreement
with those reported in the literature.1
4.1.14. (2S)-[1-(2-Hydroxy-1-(S)-phenyl-ethyl)-piperi-
din-2-yl]-acetic acid methyl ester (14). A solution of
NaBH(OAc)3 was prepared by adding NaBH4 (1.6 g,
42 mmol)) to glacial acetic acid (23.8 mL, 420 mmol))
while keeping the temperature between 10 and 208C. After
the hydrogen evolution ceased (30 min), acetonitrile
(30 mL) was added and the solution was cooled to 08C.
Compound 10 (2.32 g, 8.4 mmol) was added in one portion
and the reaction was stirred for 4 h at 08C then at room
temperature for 48 h. The solvents were evaporated in vacuo
and the residue dissolved in CH2Cl2. The organic layer was
neutralized with saturated aqueous Na2CO3 solution, dried
over Na2SO4 and concentrated in vacuo. Column chroma-
tography eluted with ethyl acetate/cyclohexane/NEt3
2:8:0.3 yielded the title compound (2.16 g, 93%) as a 95:5
mixture of diastereomers. A second chromatography
afforded the pure major diastereomer (1.45 g, 63%).
Rf¼0.26 (ethyl acetate/cyclohexane/NEt3 2:8:0.3). 1H
NMR d: 1.45–1.53 (m, 5H); 1.68–1.76 (m, 1H); 2.36–
2.57 (m, 4H); 2.65–2.73 (m, 1H); 3.56–3.70 (m, 2H); 3.65
(s, 3H); 3.75–3.82 (m, 2H); 7.24–7.34 (m, 5H). 13C NMR
d: 19.4; 25.8; 29.6; 32.0; 42.9; 51.6; 54.7; 62.2; 68.3; 127.7;
128.5; 128.6; 139.9; 173.4. [a]2D0¼þ73 (c 1.075, CHCl3). IR
4.1.11. 8a-Methyl-3-(S)-phenyl-hexahydro-oxazolo[3,2-
a]pyridine (11). Compound 10 (109 mg, 0.4 mmol) was
stirred in 1N HCl aqueous solution (15 mL) for 15 h at room
temperature. The reaction mixture was basified by careful
addition of solid Na2CO3 and extracted with CH2Cl2
(3£15 mL). The combined organic layer was washed with
brine (20 mL) dried over Na2SO4 and concentrated in
vacuo. Column chromatography eluted with ethyl acetate/
cyclohexane 2:8 yielded the title compound (82 mg, 95%)
as an inseparable 9:1 mixture of diastereomers. Rf¼0.3
(ethyl acetate/cyclohexane 2:8). The spectroscopic data of
the major one is in total agreement with those reported for
the compound with a cis relationship between the phenyl
and the methyl substituents.13 Selected data for the minor
trans isomer: 1H NMR d: 1.19 (s, 3H); 1.40–1.80 (m, 5H);
1.84–1.93 (m, 1H), 2.22–2.35 (m, 1H); 2.54–2.63 (m, 1H);

S. Calvet et al. / Tetrahedron 59 (2003) 6333–6339
6339
(neat) nmax 3430, 1725 cm21. Anal. calcd for C16H23NO3:
C, 69.29; H, 8.35; N, 5.05. Found: C, 69.35; H, 8.29; N,
5.10.
10. As a complementary experiment, methyl 7-chloro-3-oxohep-
tanoate was heated overnight in the conditions a (Na2SO4,
Na2HPO4, cat. I2) or b (Na2CO3, cat. TBAI) described above
but without any (S)-phenylethylamine. In the former case, the
starting material was recovered unchanged, whereas the
second set of conditions yielded quantitatively to a mixture
of the tetrahydropyranyl compound 4 and the partially
enolized cyclic keto ester 6 in a 46/54 ratio as determined
4.1.15. (2S)-Methoxycarbonylmethylpiperidin-1-car-
boxylic acid tert-butyl ester (16). The major isomer 14
(0.23 g, 0.83 mmol) in methanol (15 mL) was subjected to
hydrogenation 1 atm) in the presence of Pd(OH)2/C (0.11 g)
at room temperature for 4 h. The mixture was then filtered
over a Celitew pad and the solvent removed in vacuo. The
residue was dissolved in CH2Cl2 (10 mL). NEt3 (1.15 mL,
8.3 mmol) and Boc2O (0.4 g, 1.83 mmol) were successively
added. The reaction mixture was stirred at room temperature
for 15 h, then washed successively with 1N HCl aqueous
solution (2£10 mL), saturated aqueous NaHCO3 solution
(10 mL) and brine (10 mL). Drying over Na2SO4 and
concentration in vacuo was followed by column chroma-
tography eluted with ethyl acetate/cyclohexane 3:7 to yield
the title compound (0.19 g, 90%) as colourless oil. Rf¼0.29
(ethyl acetate/cyclohexane 2:8). Spectroscopic data are in
total agreement with those reported in the literature.20
[a]D20¼28.1 (c 3.615, CHCl3) {lit.,20 [a]2D0¼28.3 (c 4.54,
CHCl3) for the 2(S) enantiomer}.
1
by H NMR. This result supports the initial formation of an
enolate from methyl 7-chloro-3-oxoheptanoate.
11. For compound 6 see: Umemura, K.; Matsuyama, H.;
Watanabe, N.; Kobayashi, M.; Kamigata, N. J. Org. Chem.
1989, 54, 2374–2383.
12. Berthiaume, G.; Deslongchamps, P. Bull. Soc. Chim Fr. 1995,
132, 371–383.
´ ´ ´
13. Andres, J. M.; Herraiz-Sierra, I.; Pedrosa, R.; Perez-Encabo,
A.; Eur, J. Org. Chem. 2000, 1719–1726.
´ ´
14. (a) Bardou, A.; Celerier, J.-P.; Lhommet, G. Tetrahedron Lett.
1997, 38, 8507–8510. (b) Nikiforov, T.; Stanchev, S.;
Milenkov, B.; Dimitrov, V. Heterocycles 1986, 24,
1825–1829. (c) O’Brien, P.; Porter, D. W.; Smith, N. M.
Synlett 2000, 1336–1338. (d) Ledoux, S. PhD Thesis,
´
Universite P. et M. Curie, Paris, 2000.
15. Cimarelli, C.; Palmieri, G. J. Org. Chem. 1996, 61,
5557–5563.
References
16. Compound 12 was purified directly by crystallization from the
crude product, whereas its analogue issued from (S)-1-
phenylethylamine had to be first transformed into its picrate
salt to allow crystallization. See: Cusserne-Bardou, A. PhD
1. David, O.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Tetra-
hedron Lett. 2002, 43, 3471–3474.
´ ´
2. (a) Ledoux, S.; Marchalant, E.; Celerier, J.-P.; Lhommet, G.
Tetrahedron Lett. 2001, 42, 5397–5399. (b) Back, T. G.;
Hamilton, M. D. Org. Lett. 2002, 4, 1779–1781.
´
Thesis, Universite P. et M. Curie, Paris, 1997.
17. Crystallographic data (excluding structure factors) for the
structure of 12 has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 202748. Copies of the data can be obtained,
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk]. The X-ray analysis was performed
¨
3. Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. Helv. Chim.
Acta 1971, 54, 710–734.
4. Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61,
6313–6325.
5. Michael, J. P.; Hosken, G. D.; Howard, A. S. Tetrahedron
1988, 44, 3025–3036.
´ ´
in the Centre de Resolutions de Structures, Universite P. et
6. This compound was obtained according to a procedure
described for the analogous ethyl ester: Lambert, P. H.;
M. Curie, Paris, France.
18. Harrison, J. R.; O’Brien, P.; Porter, D. W.; Smith, N. M.
J. Chem. Soc., Perkin Trans. 1 1999, 3623–3631.
19. Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada,
Y.; Murahashi, S.-I. Bull. Chem. Soc. Jpn 2000, 73,
2423–2444.
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Vaultier, M.; Carrie, R. J. Org. Chem. 1985, 50, 5352–5356.
7. The presence of this by-product was also observed by others
authors.5
´
8. For spectral data of 5, see: Cave, C.; Daley, V.; d’Angelo, J.;
Guingant, A. Tetrahedron: Asymmetry 1995, 6, 79–82.
9. For compound 4 see: Takahashi, A.; Kirio, Y.; Sodeoka, M.;
Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1989, 111,
643–647.
20. Morley, C.; Knight, D. W.; Share, A. C. J. Chem. Soc., Perkin
Trans. 1 1994, 2903–2907.